Several lines of evidence suggest that dysfunction of serotonin neurotransmission predisposes individuals to alcohol dependence and contributes to the maintenance of excessive alcohol consumption. A variety of studies have provided evidence that serotonin neurotransmission is reduced in the brain of alcohol- dependent subjects and alcohol-preferring animals. Alcohol-dependent populations have a high lifetime suicide rate, and alcoholism is one of two psychiatric disorders most frequently found in suicidal cases. Furthermore, major depression is a frequent co-morbid condition among individuals with alcohol dependence, and suicidal behavior and depression have also been linked to alterations in serotonin. It remains unclear what neurochemical substrate or mechanism is responsible for the deficit in serotonin neurotransmission in alcohol dependence or if serotonergic regulation is further diminished in alcohol- dependent subjects with major depression that exhibit suicidal behavior. This proposal is intended to test the hypothesis that there is a deficit in serotonin neurotransmission in midbrain serotonin neurons in suicide subjects diagnosed with alcohol-dependence and major depression relative to non-suicide, non-depressed alcohol-dependent and normal control subjects which is caused by an alteration in one or more key neuronal regulators of serotonin biosynthesis. This proposal will examine gene and protein expression of several serotonin molecules including tryptophan hydroxylase, 5-HTiA receptors and specific serotonin transcription factors in the dorsal raphe nucleus of human postmortem specimens of two alcohol-use subject groups and a normal control subject group. The goals of this proposal are to understand the biochemical mechanisms underlying the deficiency in serotonin neurotransmission specifically in subjects committing suicide with alcohol dependence and co-morbid major depression. Given the seriousness, lethality and devastating consequences associated with suicidal behavior in alcohol-dependent populations, understanding the neurobiological mechanisms contributing to such harmful behavior in alcohol-dependent individuals may offer clues for developing new treatment strategies and possible avenues to prevent suicidal behavior in alcoholism. [unreadable] [unreadable] [unreadable]